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Synthetic binders based on the sequence of natural binders: real or imaginary mimicry?

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Synthetic sequence-based or structure-based epitope and paratope mimetics have repeatedly been shown to display binding activities similar to those of the antigen and antibody, respectively, from which they were derived. They were also found to reproduce some of the protein’s biological activities, such as ...

Synthetic sequence-based or structure-based epitope and paratope mimetics have repeatedly been shown to display binding activities similar to those of the antigen and antibody, respectively, from which they were derived. They were also found to reproduce some of the protein’s biological activities, such as antigen neutralization (in case of paratope mimetics) or the ability to elicit an immune response (in case of epitope mimetics).

It is widely assumed that functional mimicry implies structural mimicry, i.e. that synthetic binders form similar atomic contacts with the target as compared to their parent proteins. While it seems plausible that synthetic peptides can reproduce the structural properties of relatively mobile or simple protein binding sites, such as C- and N-termini or single loops, their ability to mimic highly structured sites such as antibody paratopes is quite challenging and therefore questionable. The typically weak target binding affinity displayed by the synthetic binders (KD in the mM to µM range) may well result from a non-discriminating bonding potential, provided in particular by non-specific hydrophobic and electrostatic interactions, combined with sufficient conformational mobility to adjust to the target surface.

Evidence on structural mimicry can be obtained directly from structural (X-ray or NMR) studies of the mimetic●target and parent molecule●target complexes, or indirectly from perturbation analysis. In the latter approach, identical chemical modifications at both interfaces should then give similar effects on complex stability and, consequently, suggest comparable interface architectures. A review of the literature indicates that such approaches are seldom applied, and that, when available, often do reveal differences in binding modes.

The demonstration of structural mimicry is a major issue to establish rational design as an appropriate strategy for developing new binders, with good chances of success compared to library screening. Furthermore, a precise understanding of the binding mode of synthetic molecules is crucial to achieve both the affinity and selectivity required for efficient activity. Because the question is centered on binding and not on biologic activity, the special topic is not restricted to the field of immunochemistry, and focuses on the binding properties of any designed peptido- or glyco-mimetic, as compared to those of its parent molecule.


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